OBJECTIVE: To define the acinar organization for bile formation and drug-induced cholestasis. Specifically, we propose to study the contribution of each cellular zone of the hepatic acinus to: a) uptake of organic anions, drugs and hormones; b) the synthesis of bile salts and c) cytochrome P-450 activity (distribution of multiple forms). Experimental Design: Uptake will be studied in vivo after selective zonal damage as well as in vitro in two isolated sub-populations of hepatocytes. These populations correspond predominantly to periportal or centrilobular cells. The ultrastructural basis for solute-membrane interaction will be studied by morphometric techniques. The contribution of acinar zones to bile salt synthesis will be determined by following the activity of cholesterol 7 alpha hydroxylase in the two liver cell sub-populations at different levels of bile salt depletion. Similarly, the distribution of the multiple forms of cytochrome P-450 in these sub-populations will be determined. The impact of drugs and hormones known to modify bile secretion will be studied in each cellular zone by following structural changes using a double embedding technique for electron microscopy.